Glaucoma is a common, blinding disease affecting 2% of Americans over the age of 40 with primary open- angle glaucoma being the most common form (70-90% of all patients). Population surveys indicate that less than half of those with glaucomatous damage have received an appropriate diagnosis or treatment. At least seven genes for POAG have been mapped, however, they represent only a small proportion of all cases. The majority of POAG results from an interaction between a person's genetic background and their environment. Identifying genes involved in complex traits, such as POAG, has been facilitated by the significant progress made by the human genome project. To tease out the potentially important genes from this complex disorder, the general phenotype of POAG will be simplified into specific endophenotypes, e.g., corneal thickness, intraocular pressure, and optic nerve cup parameters. These more discrete components will be examined within POAG families and will allow the inclusion of related members, who may not yet have POAG but have one of the above risk factors. The long-term goal of this proposal is to detect and map polymorphic genes that influence variation in risk factors for glaucoma. To provide adequate power to detect and map POAG risk factor genes, we have recruited 1500 members of 37 extended families from Northwestern US, Australia and Greece. The heritabilities will be estimated for the POAG risk factors including IOP, optic nerve and corneal thickness. An eight centimorgan map will be generated including genotyping of 500 microsatellite markers in each of the 1500 individuals. The phenotypes will be screened for linkage using the standard analysis, as well as, variance component approach. Finer scale mapping with microsatellite markers and single nucleotide poly-morphisms will more precisely localize quantitative trait loci within targeted chromosomal regions. Candidate genes within these regions will be sequenced in the 37 families to identify variations associated with specific risk factors. This study will form the basis for future studies aimed at identifying and characterizing the genes that influence POAG risk factors.